Many anticancer agents used in chemotherapy are known to cause various undesirable toxicities associated with their cytotoxic properties. It is widely known that there are many instances where such undesirable or intolerable drug related toxicities impose crucial limitations on the dose and schedule for administration of such antineoplastic agents to patients with cancer. It is notable to consider that the drug induced toxicity associated with many cancer chemotherapy drugs can offset the potential benefit to the patient undergoing treatment since the development of chemotherapy induced toxicity can result in delaying treatment, or in severe cases, lead to the discontinuance of treatment altogether. These two outcomes can allow the patient's cancer to progress unchecked or to limit the opportunity to cure or significantly palliate the patient's disease by limiting the dose, duration or schedule of chemotherapy treatments that are aimed at curing or palliating the patient's cancer.
It is well known that such antineoplastic agent-induced toxicities vary with antineoplastic agent species or class that are well recognized by experts. Furthermore, adverse events or toxicities produced by such anticancer drugs are based on a diversity of biochemical and pharmacological mechanisms that may be entirely different from one another even though superficially, the patient's symptoms and signs are apparently identical or similar in terms of the nature of their description. Therefore, it is also known that it is not necessarily a reasonable expectation to prevent or to mitigate all such undesirable toxicities associated with all chemotherapy agents or to inhibit their side effects non-selectively. Drug related side effects occur in vivo upon administration of a specific antineoplastic agent based on the toxicities common to that antineoplastic agent, and observed patient side-effect symptoms vary according to diverse factors and sensitive natures per in vivo tissue, cell or organ and the interaction with other drugs that are administered. Accordingly, the safe and effective means for solving such problems will vary. Of course, it is important to recognize that an ideal chemoprotective agent is one that would not result in an additional separate or additive toxicity to the patient in conjunction with the administration of chemotherapy; this is one of the novel objects of the current invention.
Representatives of taxane antineoplastic agents are paclitaxel, docetaxel, and others currently in clinical and pre-clinical development. Such taxane antineoplastic agents have been frequently and widely employed to treat patients with breast cancer as well as patients with ovarian, lung, bladder, esophagus, and other sites of origin in the United States, Europe Japan and other countries. However, the administration of taxanes requires precautions because serious and potentially life threatening side effects often occur. In particular, the clinical use of taxanes is frequently delayed or discontinued altogether due to toxicities causing the disorder of peripheral nerve systems (including peripheral neuropathy) such as numbness in the extremities, paresthesias, weakness, paralysis, arthralgia, myalgia, as well as others. In these instances the taxane medication treatment must be suspended, the dose of taxane chemotherapy reduced, or in the more severe cases, it is discontinued because of the neurotoxicity. Halting treatment or altering the dosage of the taxane may be detrimental to the patient's chances of long term survival or control of the cancer, since it is well known that the delay, reduction in dose or the discontinuance of chemotherapy allows the unopposed progression of the patient's cancer. Therefore, a safe and effective solution for preventing or reducing the likelihood of such common and clinically important problems relating to chemotherapy induced neurotoxicity is eagerly demanded since it is estimated that approximately 60% of patients receiving taxane chemotherapy can develop drug induced neurotoxicity.
Up to the present, various attempts have been attempted to mitigate, but not prevent the toxicities of antineoplastic agents. It is notable that there is no currently approved drug therapy that has been demonstrated in patients to be safe and effective in preventing taxane induced neurotoxicity. The treating physician basically has three treatment options: 1) delay treatment until the toxicity resolves to an acceptable level; 2) reduce the dose of taxane chemotherapy; and 3) discontinue treatment with the taxane altogether. The treating physician can employ any combination of 1 and 2 together and option 3 is reserved for more severe cases of taxane neurotoxicity. A variety of new approaches to prevent or mitigate taxane-induced neurotoxicity have been pursued more recently.
Representatives of platinum analogue antineoplastic drugs include cisplatin, carboplatin, oxaliplatin, and others in both clinical and preclinical development. Like the taxanes and many other antineoplastic drugs, platinum analogue antineoplastic drugs are associated with a number of toxicities, including nephrotoxicity, bone marrow suppression, neurotoxicity, and others.
The present inventors have filed patent applications disclosing the use of 2,2′-dithiobis ethane sulfonate and other dithioethers in order to alleviate cisplatin induced toxicity, i.e., nephrotoxicity (U.S. Pat. Nos. 5,789,000; 5,866,169; 5,866,615; 5,866,617; 5,902,610 and others . . . JP, A, 10-509143 (1998)) and carboplatin induced toxicity, i.e., myelosuppression, and also vomiting (U.S. Pat. No. 6,037,336; JP, A, 2001-500872 (2001)). The present inventors have also pointed out that 2,2′-dithiobis ethane sulfonate and dithioethers are applicable to mitigation of toxicities mediated by various antineoplastic agents (U.S. Pat. Nos. 5,919,816; 6,025,488; 6,040,294; 6,040,304; 6,040,312; 6,043,249; 6,046,159; 6,046,234; 6,048,849; 6,057,361; 6,066,645; and 6,066,668; WO 99/20264).
In the above WO 99/20264 and U.S. Pat. No. 5,919,816, a very broad range is disclosed for dose rates of dithioethers to taxane antineoplastic agents, i.e., the weight-to-weight ratio of taxane antineoplastic agent to dithioethers is from 1:4 to 1:4,000 for parenteral administration routes; however, with regard to dithioethers, the optimum dosage for use in humans has not been fully determined and is expected to be highly variable because of the wide variability of doses and schedules of chemotherapy agents that are used alone and in combination with different treatment regimens for cancer patients.
The process for synthesizing the dithioethers is outlined in U.S. Pat. No. 5,808,160 and others.